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By administering IL-21 order 10mg glucotrol xl with visa diabetes zentrum wandsbek, the protective function of the intestine could be recovered by increased Th17 cell numbers in SIV-infected rhesus macaques (Pallikkuth 2013) discount glucotrol xl 10mg line diabetes mellitus life expectancy. Humoral immune response New B cells are formed in the bone marrow throughout life buy 10 mg glucotrol xl mastercard diabetic ice cream. When mature B cells form glucotrol xl 10 mg diabetes high blood sugar symptoms, they leave the bone marrow and migrate to the secondary lymphoid organs (e. After antigen challenge, a further maturation phase ensues, which leads to the formation of the humoral immune response. Newly derived plasma cells produce diverse antibodies. The recombination of the light or heavy chains of the immunoglobulins is very similar to the process of rearrangement of the T cell receptors. A distinction is made between neutralizing and non-neutralizing antibodies. Neutralization is considered the main mechanism to combat a pathogen and is mediated either by blocking a cellular receptor or by blocking the fusion of the virus (Corti 2013). Non-neutralizing antibodies help protect against pathogens, e. Natural HIV infection first induces non-neutralizing antibodies (nNAK) and neu- tralizing antibodies (NAK) which are specific for a certain viral strain. These can be detected soon after infection (via HIV testing). However, the virus is always one step ahead of these antibodies by developing escape mutations. This leads to the diver- sification of Env in early infection (Frost 2005). These antibodies barely contribute to the control of viremia. In recent years, however, the discovery of broadly neutralizing antibodies (bNAK) led to new optimism. Up to 20% of all infected individuals build bNAK during the course of disease that can reach various strains of HIV effectively. However bNAK occur relatively late in the disease process, a minimum of two years after infection (Kwong 2013). The target of bNAK is the viral spike of the HIV-1 viral envelope, a heterodimer consisting of trimeric gp120 and the transmembrane glycoprotein gp41. Most bNAK bind to one of the following four binding sites (Kwong 2012): •antibodies directed against the CD4 binding site that recognize the binding site of the CD4 receptor to gp120; •antibodies directed against the variable region of V1 or V2 that often recognize glycopeptide epitopes near amino acid Asn160 on gp120; •antibodies directed against V3 that recognize epitopes that contain the amino acid Asn332 within gp120; and •antibodies directed against the membrane-proximal external region (MPER) that recognize a position of gp41 proximal to the transmembrane region. Interestingly, it is important that the antigen does not remain preserved continuously. Maturation of bNAK is achieved best by constantly changing Env sequences. It is this matura- tion process which is so difficult to induce by vaccination, which remains an impor- tant goal. In addition, the maturation process takes months to years (Gray 2011). The reasons for this are: •first, HIV infection itself leads to an impaired immune response •second, it may be due to Env because healthy adults who are vaccinated with an Env vaccination rarely produce bNAK •third, most likely the co-evolution of virus and immune response contributes to the emergence of bNAK. Interestingly, some bNAKs arise only due to a sequence representing an escape muta- Pathogenesis of HIV-1 Infection 39 tion (Kwong 2013). Attempts to induce bNAK by vaccination were unsuccessful. This is certainly due to the fact that the right immunogen has not been found yet. However, research is very intense in this field (Kwong 2013). In addition to the induction of bNAK by vaccination, bNAK can be passively trans- ferred in order to control infection. This has been successfully done in humanized mice and in macaques (Moldt 2012, Horwitz 2013). Despite the euphoria surrounding bNAK, it should be noted that several studies in elite controllers detected bNAK to a lesser degree than in viremic pro- gressors (Bailey 2006, Pereyra 2008, Lambotte 2009, Doria-Rose 2010). Other studies have also shown that a wider range of bNAK is typically associated with higher viral load and that this does not protect against disease progression (Deeks 2006, Sather 2009, Euler 2010). Mucosal immunity Since HIV infection is usually transmitted via the mucous membrane (mostly vaginally or rectally), the immune system of the mucous membranes needs to be mentioned. The gut-associated lymphoid tissue (GALT) is the largest immune organ of the body. Due to its high content of CD4 cells, the GALT is also the main target for HIV. The massive CD4 T cell depletion during early HIV infection leads to the microbial translocation which in turn leads to increased immune activation (Brenchley 2004+2006). The latter is pathognomonic of chronic HIV infection. However, the T cell response of the mucosa was found to be a correlate for the control of viremia in recent years (Shacklett 2011). In the mucous membranes, virus-specific T cells among others can be found. HIV-specific CD8 T cells were detected in abun- dance in the rectal mucosa as demonstrated in chronically HIV-infected individuals (Shacklett 2003, Ibarrondo 2005). Here a correlation between viral load and poly- functionality of the CD8 T cell responses could be demonstrated (Critchfield 2008). Elite controllers had significantly higher CD8 T cell responses with more effector functions in the rectal mucosa than progressors, whereas no difference in the CD8 T cell responses in peripheral blood was found (Ferre 2009). This shows that many controllers have strong, polyfunctional CD8 (and also CD4) T cell responses in the intestinal mucosa – a fact that is not reflected in the peripheral blood. Polyfunctional CD4 T cells also correlate with a high CD4 cell count and a good control of viremia, but the CD4 T cells were only non-specifically stimulated in the respective studies (Loke 2010). NK cells were shown to be reduced in the intestine in chronic HIV infection. However, a subset of these cells remained stable in controllers. Interestingly, intestinal NK cells were significantly increased in patients who did not achieve a complete CD4 T cell recovery after the start of suppressive ART. In this situation, NK cells might expand in the gut in an effort to compensate for the CD4 cell loss (Sips 2012). In ART-naïve patients, it was demonstrated that pDCs accumulate in the terminal ileum and are accompanied by elevated levels of interferon-alpha. In that way pDC could con- tribute to the development of immune activation. Both parameters were normalized after the start of ART (Lehmann 2014). Another aspect of mucosal immunity is the fact that the intestinal mucosa is an important reservoir of HIV. Two large studies have shown that in patients with effec- tive ART and a viral load below 40 HIV RNA copies/ml HIV continue to be detectable in the intestinal mucosa (Chun 2008, Yukl 2010). So far, proviral DNA has not been studied in the gut in controllers or elite controllers. The fact that strong T cell responses can be detected in this compartment in patients with good control of HIV viremia is an indirect indication that antigen can still be found. T cell responses tend to grow weaker up to undetectable when the antigen disappears (Ferre 2009 + 2010).

In the that of full-length rFVIII in terms of activation by thrombin buy 10 mg glucotrol xl otc diabetes symptoms hunger, process generic 10 mg glucotrol xl visa diabetes diet education handout, the endosome is acidified to promote binding of the thrombin generation assay purchase 10mg glucotrol xl free shipping diet plan 4 diabetic patient, and tail-clip bleeding in FVIII-deficient mice order 10mg glucotrol xl visa diabetes symptoms muscle pain. Upon recycling of the endosome to the cell surface, the Fc-fusion protein is released into the circulation under the neutral pH conditions. In this manner, the Fc-fusion Another new FVIII molecule in clinical trials is expressed in a human cell protein escapes degradation by the lysosome. This mechanism is line based on the hypothesis that the immunogenicity of the FVIII is less proposed to provide the greater T of IgG in the blood compared than for FVIII produced in the currently available mammalian, nonhuman 1/2 with other antibody isotypes. Host cell lines used for recombinant protein expression differ in examples of very effective long-acting Fc-fusion proteins. Although their ability to perform posttranslational modifications. For rFVIII, glycosy- lation and sulfation are vital for functionality and VWF-binding affinity. Fusion of the monomeric form of the IgG1 Fc to human recombinant human FVIII (human-cl rhFVIII) avoids expression of FIX, FVIIa, and B-domain–deleted FVIII by Biogen Idec has undesirable mammalian glycoforms such as Gal 1-3Gal 1-GlcNAc-R demonstrated increases in plasma T. Monomeric Fc fusion to ( -Gal) and N-glycolylneuraminic acid (Neu5Gc), which constitute epitopes 1/2 antigenic to humans. In a recent study, the human-cl rhFVIII was sulfated B-domain–deleted FVIII did not alter its specific activity and and glycosylated comparably to human plasma-derived FVIII and was displayed a 2-fold longer T1/2 in mice and dogs. The increased T1/2 devoid of the antigenic Neu5Gc or -Gal epitopes observed in Chinese requires the FcRn. The molecule showed a similar efficacy in tail 44,45 hamster ovary and baby hamster kidney–derived rFVIII products. The fusion protein complete sulfation are proposed to lower the intrinsic immunogenicity of shows an 2-fold increase in sustained protection of the WBCT. In human-cl rhFVIII compared with current rFVIII products. The clinical a phase 1 human study in 16 severe hemophilia patients, a single trials in progress should provide more information on these novel dose of FVIII-Fc demonstrated functional activity, with a 1. IV infusion of A major concern in hemophilia A is the development of neutralizing FIX-Fc into mice and dogs demonstrated a 3- to 4-fold increase in antibodies (inhibitors) that prevent further use of therapeutic FVIII. In mice, the WBCT was twice as long at the same dose of rFIX. The current options are immune tolerance therapy which is success- The pharmacokinetics and safety of this molecule were studied in ful 70% of the time, and the use of bypassing agents such as previously treated adults with severe hemophilia B. No adverse activated prothrombin complex concentrate or activated FVIIa, both events or antibodies were detected. Therefore, there are significant potential implications as the clinical trials with the new therapies develop. It Another fusion approach to increase the plasma T1/2 is to covalently may prove clinically important that FVIII produced by a human cell attach the clotting factor to albumin. Albumin linkage to coagula- line will have a lower rate of inhibitor development. It may be tion factors FVIIa and FIX (rVIIa-FP and rIX-FP, respectively) discovered that one or more of the extended T1/2 products will have increases the plasma T1/2 and the proteins display similar hemostatic a lower inhibitor rate. These issues will only be resolved over the efficacy compared with the respective recombinant factors. Clinical coming years through careful monitoring for inhibitor formation in evaluation is in progress by CSL Behring, with encouraging the current and planned clinical trials. It is Recombinant-derived FVIIa is safe and effective for treatment of possible that FVIII fusion to albumin may reduce its activity or the bleeding episodes in hemophilia patients with inhibitors, and FVIIa Hematology 2013 33 infusion has not produced neutralizing antibodies in hemophilia efficacy in vitro and in vivo in mouse models. Each type of inhibitor patients, probably because they have native FVIIa and do not of TFPI provides unique advantages and interactions with clotting recognize the infused FVIIa as foreign. Further studies in bleeding episodes compared with on-demand therapy without animals and humans will be needed to sort out the therapeutic significant safety concerns. With the current patent on NovoSeven due to expire in 2015, Targeting antithrombin several pharmaceutical companies have development programs to In another novel approach Alnylam Pharmaceuticals is developing generate molecularly modified FVIIa molecules with a longer T1/2 ALN-AT3, a synthetic, GalNAc-conjugated RNAi therapeutic de- and/or with improved efficacy. The 2 programs with the most signed to suppress liver production of antithrombin (AT) mRNA clinical trial data to date are based on molecular constructs that when administered via subcutaneous injection. Reducing AT levels introduce conservative amino acid substitutions into native FVIIa. ALN-AT3 is being developed for the treatment of patients with These early results will need much further investigation for their full hemophilia A and B. In pharmacology studies, subcutaneous explanation, but serve as a possible warning for clinical trials for administration of ALN-AT3 resulted in dose-dependent and revers- future mutations of clotting factors. In a microvessel laser clinical development involve replacement of modified versions of injury model used to compare stable thrombus formation in FVIII, FIX, and FVIIa, there are also several novel approaches hemophilia A and B mice, functional improvements in hemostasis being pursued in preclinical work. These novel approaches are were observed upon treatment with ALN-AT3. Animals adminis- intriguing, but much remains to be determined as they enter clinical tered a single dose of 1 or 30 mg/kg ALN-AT3 10 days before injury development. Stable Factor Xase complex mimetics hemostatic plug formation was observed at all sites of injury in FVIII acts to increase the Vmax and decrease the Km for FIXa- treated animals, whereas no stable hemostatic plugs were observed mediated cleavage of FX in the presence of negatively charged in any of the injury sites in untreated animals. Current efforts are directed toward identifying small mol- Extensive toxicology studies have been conducted in several species ecules to replace the FVIII dependence by promoting the assembly to support clinical development of ALN-AT3. As expected, the of FIXa and FX on a negatively charged phospholipid surface in a toxicity observed in wild-type animals is primarily attributable to manner that stimulates the rate of FXa generation. The availability the exaggerated on-target, procoagulant pharmacology of ALN- of such a molecule would dramatically affect hemophilia care by AT3. Specifically, 90% AT reduction in wild-type animals providing agents that could be delivered subcutaneously or even typically resulted in adverse thrombotic events and disseminated orally. A humanized bispecific mAb to FIXa and FX was derived intravascular coagulation. In contrast, exaggerated exposures of (hBS23) that displayed a 2-week T1/2 in a cynomolgus monkey ALN-AT3 (doses up to 500 mg/kg and 95% reduction in AT) model of acquired hemophilia. This rebalancing an impaired hemostatic system and demonstrate an suggests that small molecules with similar potential that could be expanded therapeutic index in the disease condition. Inhibition of antithrombotic pathways The tissue factor/FVIIa/FXa complex forms small amounts of Conclusion thrombin to initiate coagulation. Tissue factor pathway inhibitor The past quarter-century has witnessed a tremendous expansion in (TFPI) inhibits this complex by interaction of its 2 Kunitz domains. Kunitz domain 1 interacts with FVIIa and Kunitz domain 2 interacts These advances, together with greater knowledge of the mecha- with FXa. A mAb to the second Kunitz domain neutralizes the nisms that define protein clearance in the plasma, have led the way inhibitory effect of TFPI on extrinsic pathway activation. Subcuta- to several clinical trials for potentially improved clotting factor neous administration of this mAb (mAb 2021) 24 hours before products for persons with hemophilia A or B. New extended T1/2 injury prevented bleeding in hemophilic rabbits. In addition, there may be alternative approaches aptamer that binds tightly and specifically to TFPI and inhibits its to preventing bleeding in hemophilia that will soon be entering function in vitro and in vivo. Future questions include: (1) how will the costs of anticoagulant sulfated polysaccharide (NASP) BAX 513 that dem- these new factor products influence their clinical use; (2) will there onstrated efficacy in hemophilia dogs. Enthusiastic participation by physicians and patients associated virus vector-mediated gene transfer in hemophilia B. Characterization of a genetically engineered inactivation-resistant coagulation factor VIIIa.

A recent risk-adjusted cheap 10mg glucotrol xl overnight delivery diabetes type 2 pregnancy, propensity- matched buy glucotrol xl 10 mg line metabolic disease in dogs, case-control study of outcomes of all hospitalized patients who refused ABT at a large academic health center showed that bloodless management was not an independent predictor of adverse outcomes glucotrol xl 10 mg free shipping diabetic diet recipes to lose weight. Surprisingly buy discount glucotrol xl 10mg gestational diabetes definition who, there was a lower overall mortality in the bloodless group and discharge hemoglobin levels were similar for both bloodless and control groups. Further research is now needed to optimize therapy and identify novel interventions to manage bloodless patients. Lessons learned from bloodless patients are likely to benefit all patients given recent evidence suggesting that patients who avoid ABTs do as well, if not better, than those who accept transfusions. The majority of JW ● To outline currently available approaches to manage anemia patients will agree to accept these products because they are or bleeding in “bloodless patients” considered to be “minor blood fractions” according to their religious ● To discuss areas in need of further research to advance doctrine. Importantly, the JW faith currently includes 8 million bloodless medicine people worldwide, with 1. As discussed here, these Introduction patients provide a unique challenge to health care providers, Although blood transfusions are among the most common medical particularly when presenting for surgeries or invasive procedures procedures performed in hospitalized patients, a better understand- that can be associated with significant blood loss or for complex ing of transfusion risks, together with a growing population of medical illnesses. Here, we outline prior studies on bloodless management and discuss the ap- At most centers, the majority of patients who request bloodless proaches used at our institution to care for patients who refuse medicine are members of the Jehovah’s Witness (JW) faith. We close Based on religious beliefs, these individuals do not accept blood with suggestions for further studies to guide management of products considered to be “primary components,” which includes bloodless patients. Because recent evidence suggests that bloodless RBCs, WBCs, platelets, or plasma. A few are to diagnose and treat anemia and minimize blood loss. Surgical subsequent studies used a propensity-matched control group, which patients who present for preoperative evaluations should be screened is a statistical matching technique that attempts to account for for both anemia and bleeding diatheses. The prevalence of anemia confounding variables and decrease bias associated with these in patients who present for elective surgery is highly variable, 9,11,15 variables. The majority of studies with propensity-matched ranging from 5% to 75% depending on the patient population, 9,11,15 18 controls, however, have focused on cardiac surgery. Interest- underlying pathology, and definition of anemia. The World Health ingly, 2 of these studies reported similar outcomes between patients Organization defines anemia as a hemoglobin 12 g/dL for women 11,15 who accept ABT compared with those who do not. Moreover, a and 13 g/dL for men, which provides useful guidelines for most 18 recent study of cardiac surgery patients and a propensity-matched patient populations. Ideally, the diagnosis of anemia should be control group actually showed a lower incidence of myocardial made at least 4-8 weeks before an elective procedure to ensure infarction and reoperation for bleeding in the bloodless patient adequate time for evaluation, therapy, and correction of the 9 4,8 group. There were also shorter durations of mechanical ventilation, anemia. This proves to be a challenge for many institutions, shorter length of both ICU and total hospital stays, and better 1-year because preoperative evaluations are often done less than 1 week survival in the bloodless patients. Iron deficiency is the most common form of anemia that bloodless management can yield similar, and possibly better, worldwide and is often associated with renal insufficiency and outcomes for a subset of patients. Not surprisingly, anemia is a academic health center found similar outcomes in bloodless patients significant predictor of RBC transfusion in patients who accept 18 compared with expected outcomes based on Society of Thoracic ABT. Intriguingly, recent evidence suggests that RBC transfu- 8 Surgeons risk models and historical controls. The favorable sions to treat anemia is an additive risk factor for adverse outcomes 18 outcomes were observed for both elective and urgent cardiac independent of the anemia itself. Although the average age for all patients in this study was are relatively common and can be associated with both anemia and 19 slightly younger (63. Patients with VWD 21 studies, this report describes a practical approach to patients can be managed with desmopressin (DDAVP) or VWF concentrates 8 19 undergoing bloodless cardiac surgeries. All patients were evaluated (Humate-P or cryoprecipitate) if acceptable to the patient. In by a “bloodless team” and consented for an itemized list of blood addition, many patients take drugs or supplements that interfere products they would accept or refuse. Details of laboratory evalua- with platelet function and can cause excessive bleeding, such as tions were not described, but anemia was managed preoperatively cyclooxygenase inhibitors (aspirin, celecoxib, etc) or platelet adeno- with intravenous iron supplementation and subcutaneous erythropoi- sine diphosphate receptor (P2Y12) inhibitors (clopidogrel, prasug- etin (40 000-60 000 IU/week) to achieve a target hemoglobin of rel, etc). Therefore, patients on these agents are instructed to stop 14-16 g/dL or a measure that correlates with RBC volume (RCV) them before surgical procedures. Similarly, elderly patients with 8 (Hb body weight in kilograms) of 1200. The target value of 1200 atrial fibrillation are frequently on anticoagulation therapy such as was chosen because the investigators noted an increased risk for warfarin, and need to receive appropriate counselling regarding ABT in patients with a value 800 who were hospitalized at their when to stop these agents and whether they will require shorter- institution. In addition, lower hemoglobin levels were tolerated in acting, bridging agents such as low-molecular-weight or standard larger patients, for whom this value was 1200. If elective cardiac catheterizations were done, they were Limiting phlebotomy for laboratory testing is important because this performed 3 weeks before surgery to allow recovery from procedure- is frequently a source of significant blood loss, particularly in 8 related anemia when possible. For surgeries needed within 48 patients hospitalized in intensive care units (ICUs). In fact, it is hours of cardiac catheterization, a vascular closure device was estimated that ICU patients can lose up to 1% of their blood volume recommended to reduce blood loss. Acute coronary syndromes were each day from phlebotomy alone, which becomes significant with 20 managed medically, followed by coronary artery stent placement. Pediatric or low-volume microtainer tubes Patients were evaluated for bleeding risk factors and advised to can be used to minimize the volume of blood needed for laboratory discontinue use of alcohol and medications or supplements associ- testing, although they need to be manually inserted into the ated with an increased bleeding. Before surgery, aspirin (3-5 days) laboratory instruments, which requires more effort by laboratory and clopidogrel (7 days) were withheld. Postoperative surgical patients with simple outcome measures, such as length of care included warming patients to normothermia and avoiding stay and mortality, without matched control groups for compari- hypertension. If tolerated hemodynamically, positive end-expira- son. Methods of blood conservation for “bloodless medicine” to a patient) were used to maintain euvolemia. Cryoprecipitate or recombinant Low-volume microtainers for phlebotomy factor VIIa was used for bleeding unless patients were undergoing Tolerating lower hemoglobin levels coronary artery bypass, in which case factor VII was avoided. A low Diagnosing and treating anemia or other cytopenias threshold was recommended for reexploration if surgical bleeding Methods relevant only to surgical patients was suspected. Phlebotomy was minimized with low-volume tubes Early diagnosis and treatment of preoperative anemia for laboratory blood testing, point of care testing, and in-line blood Intraoperative autologous blood salvage draw systems. Coagulation profiles were avoided unless patients Intraoperative autologous normovolemic hemodilution were suspected of active bleeding. Erythropoiesis-stimulating agents Meticulous surgical technique Perioperative antifibrinolytics (tranexamic acid, epsilon aminocaproic (ESAs) were administered in some cases, although more specific 8 acid) details were not provided. The comorbidities in JW patients were New methods of electrocautery similar to a large 2012 study of cardiac surgery patients, except for 20 Topical sealants and hemostatic agents renal failure, which was less common in the bloodless patients. Avoiding perioperative hypothermia Nonetheless, the JW patients undergoing either elective or urgent Intentional moderate hypotension cardiac surgery had similar outcomes to historical controls. Even patients who accept blood products may not be consid- comparing concurrent, non-risk-adjusted pregnant women showed a ered surgical candidates if premorbid conditions are thought to be 44-fold greater maternal mortality for patients who refused ABT associated with unacceptable surgical risks. Therefore, future stud- compared with patients who accept ABT. Further studies are Our recommendations for bloodless medicine needed to determine whether the estimated increase in mortality is Based on prior reports and our experience thus far, we follow 5 relevant to a more diverse patient population. We request establishing a Bloodless Medicine and Surgery Program to care for that all surgical patients seeking bloodless care obtain a preopera- such patients at our institution, we reported a risk-adjusted, propen- tive complete blood count as soon as possible, preferably at least 4-8 sity-score-matched retrospective case-control study of clinical out- weeks before the surgery. We typically recommend oral iron (325 comes for hospitalized patients who did not accept ABT (bloodless mg ferrous sulfate; 2-3 doses/day as tolerated) and a multivitamin patients; n 294) compared with a control group of patients supplemented with B12 and folate after we identify a patient (control patients, n 1157). Each bloodless microcytic or normocytic anemia is present, iron studies are patient was matched by associated risks to 4 control patients to recommended (ferritin, transferrin saturation, total iron binding increase the sample size and power to detect differences.

Ensure that the apply acetic acid (white vinegar) during each specu- woman has understood and obtain informed lum examination that is performed for any other consent best glucotrol xl 10mg diabetes type 1 foot problems. Adjust the light source in order to get the best view of the cervix buy glucotrol xl 10mg mastercard diabetes symptoms 18 month old. Use a cotton swab to remove any discharge generic glucotrol xl 10 mg on-line most popular diabetes medications, Visual screening method blood or mucus from the cervix buy glucotrol xl 10 mg without prescription blood glucose range for diabetics. In VIA we inspect the transformation or transition 5. Apply acetic acid or Lugol’s iodine to the epithelium of the uterine cervix). In a visual test, cervix; wait a minute or two to allow color the provider applies acetic acid (in VIA) or Lugol’s changes to develop. Observe any changes in iodine solution (in VILI) to the cervix, and then the appearance of the cervix. A VIA test is attention to abnormalities close to the transfor- positive if there are raised and thickened white mation zone. Inspect the SCJ carefully and be sure you can positive if there are mustard or saffron-yellow see all of it. Either test is suspicious for cancer if a plaques or aceto-white epithelium if you used cauliflower-like fungating mass or ulcer is noted on acetic acid or saffron-yellow colored areas after the cervix. Visual screening results are negative if application of Lugol’s iodine. Remove any the cervical lining is smooth, uniform and feature- blood or debris appearing during the inspec- less; it should be pink with acetic acid and dark tion. For a schematic overview of the test, brown or black with Lugol’s iodine. Figure 7 shows examples of 324 Cervical Cancer Prevention and Treatment (a) Figure 6 Schematic overview of the cervix and the aceto-white area. Courtesy of Screening Group (SCR), International Agency for Research on Cancer (WHO- IARC) a negative and positive VIA tests and non- invasive cervical cancer. Use a fresh swab to remove any remaining (b) acetic acid or iodine solution from the cervix and vagina. Draw a map of any abnormal findings on the record form. A sample of a record form and map can be found at: http://screening. Discuss the results of the screening test with the patient. If the test is negative, tell her that she should have another test in 3 years. If the (c) test is positive or cancer is suspected, tell her what the recommended next steps are. If she needs to be referred for further testing or treat- ment, make arrangements and provide her with all necessary forms and instructions before she leaves. Other diagnostic tests Biopsy Biopsy is the removal of small areas of the cervix for histopathological diagnosis. It should be done with a punch biopsy forceps (Figure 8); one or more small pieces of tissue (1–3 mm across) are removed Figure 7 Examples of (a) negative (note no aceto-white from the abnormal areas of the cervix identified by areas seen) and (b) positive (note the well-defined opaque colposcopy or VIA (see Chapter 1 on gynecological aceto-white lesion in the anterior lip arising from the SCJ) examination on how to do a biopsy). Bleeding is VIA tests and (c) non-invasive cervical cancer (note dense usually minimal. The samples are placed in a pre- aceto-white area with irregular surface contour). Courtesy servative, such as formalin, and the container of Screening Group (SCR), International Agency for labelled. This is then sent to a laboratory for precise Research on Cancer (WHO-IARC) histopathological diagnosis of the abnormalities, 325 GYNECOLOGY FOR LESS-RESOURCED LOCATIONS patients can be followed up with colposcopy and cytology every 6 months until the lesion regresses to normal, or there is evidence of progression of the abnormality. If progression is noted, or in cases where follow-up is problematic, as well as in older women in whom spontaneous regression is less Figure 8 A cervical biopsy forceps. Source: Compre- likely, immediate treatment should be considered. Geneva: WHO, 200639 Special considerations Pregnancy whether they are pre-cancer or cancer, and their severity and extent, so that treatment can be tailored Women known or suspected to be pregnant should to each case. A biopsy should be performed: not be treated for pre-cancer; they should be advised to return at 12 weeks post-partum for further evalu- • On women with an abnormal screening test ation. If invasive cancer is suspected, the patient • If suspicious lesions are seen on the cervix on should be referred immediately to a specialist. Women who present for treatment during men- Endocervical curettage struation can be treated if the bleeding is slight. It is advisable to delay the procedure if menstruation is If a woman has a positive Pap test, but no abnormal heavy and interferes with visualization of the extent areas are observed with colposcopy, there may be a of the lesion. However, it is important to remem- lesion in the cervical canal. In this case, the endo- ber that she may be bleeding because of cervical cervix can be examined with a special speculum cancer, so an examination should not be deferred and a sample of cells can be obtained with an endo- for longer than a week. Endo- cervical curettage is a simple procedure, in which The woman has a cervical infection or pelvic some of the surface cells are gently scraped from the inflammatory disease cervical canal (See Chapter 1 on gynecological ex- • A cervical infection with no evidence of pelvic aminations). For more information and digital pub- inflammatory disease (PID) (diagnosed clinically lications see http://www. If LEEP or cold knife TREATMENT OF PRE-MALIGNANT conization is to be used, the infection must be LESIONS treated before the procedure. Pre-malignant lesions of the cervix can be treated • If PID is suspected, a full course of appropriate with either cryotherapy, LEEP of cold knife coni- antibiotic treatment should be completed prior zation. In this chapter we describe them with indi- to any treatment (see Chapter 17 on STI). If you want thorough • Whenever a woman is treated for a cervical in- knowledge about the subject you can download fection, with or without PID, her partner also the following publications for free: http://screen- needs to be fully treated to prevent reinfection. Condoms and instructions on their Indications for treatment use need to be provided to all such patients. All biopsy-confirmed CIN 2 and 3 lesions should The woman is HIV infected be treated, because the majority of them persist and may eventually progress to invasive cancer. CIN 1 HIV-positive women should be managed in the is more likely to resolve spontaneously; these same manner as uninfected women. However, 326 Cervical Cancer Prevention and Treatment HIV-positive women are known to have higher 1. Explain the procedure, and why it is important rates of persistence, progression and recurrence of to return for further management as requested. Women with HIV infection Ensure that the woman has understood and should therefore be monitored every 6 months obtain informed consent. Show her the cryotherapy equipment and ent, progressive or recurrent high-grade lesions are explain how you will use it to freeze the detected. At present there is no clear evidence on abnormal areas on the cervix. Prepare the patient for a gynecological exami- drugs modifies regression or progression of cervical nation, and perform a speculum. If there is no evidence of infection, proceed Before any treatment, HIV-positive women with cryotherapy. If there is a cervical infection, provide treat- understand the need for close follow-up, and the ment (see Chapter 17 about STIs). You may possibility of need for repeat treatments, as well as proceed with the cryotherapy, or you may give the potential for increased transmission and acquisi- the patient an appointment to return once the tion of STIs and HIV during healing. Wipe the cervix with a saline-soaked cotton swab and wait a few minutes.

Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Co untry Studydesign TrialName Setting Eligibilitycriteria Interventio ns Run-in/washo utperio d H ill Ra nd om ized discount 10 mg glucotrol xl mastercard diabetes insipidus high urine specific gravity,d oub le- Child ren a ged 7-17yea rs 10mg glucotrol xl with amex diabetes type 2 new medication,c hronic Intra na sa lb ec lom etha sone NR/NR 1978 b lind cheap glucotrol xl 10 mg overnight delivery diabetes type 2 patho,c ross-over cheap glucotrol xl 10mg online managing diabetes in dogs,p la c eb o-m outh-b rea thers with gross d ip rop iona te,300m g/d a yvs c ontrolled hyp ertrop yofna sa lm uc osa a nd p la c eb o single-c enter exc essive rhinorrhea ,fa iling to S tud yp eriod :NR resp ond to a ntihista m ines a nd a d rengic d rugs Na ya k Doub le-b lind ,p la c eb o- Child ren a ged 6-12yea rs with tria m inolone a c etonid e a q ueous NR/NR 1998 c ontrolled a llergic rhinitis,m a les a nd na sa lsp ra y220g onc e d a ilyvs m ultic enter p rem ena rc hea lfem a les 440g onc e d a ily Exc lusion:c linic a llyrelelva nt S tud yp eriod :6weeks d evia tion from norm a lm ed ic a lor la b p a ra m eters,intolera nc e to c ortic osteroid thera p y,a ny m ed ic a lc ond ition c a p a b le of a ltering p ha rm okineti NCS Page 287 of 357 Final Report Update 1 Drug Effectiveness Review Project EvidenceTable7. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Metho do fo utco me Age Numberscreened/ Co untry Allo wedo thermedicatio ns/assessmentandtimingo fGender Otherpo pulatio n eligible/ TrialName interventio ns assessment Ethnicity characteristics enro lled H ill No d rugs used forrhinitis Da ilysym p tom d ia ryresults 7-17yea rs Assoc ia ted rec urrenta sthm a :12/22 NR/NR/22 1978 a llowed d uring stud yp eriod rec ord ed a tc linic visits 50% Fem a le Evid enc e ofm a rked system ic a llergy Ethnic ityNR to house d ustm ite a nd /orrye gra ss Na ya k NR/NR Ad renoc ortic a lfunc tion 9. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Number Co untry withdrawn/ Metho do fadverseeffects TrialName lo stto fu/analyzedOutco mes assessment H ill 0/0/22 Num b erofc hild ren with resp onse: Pa tientd a ilysym p tom d ia ry 1978 Na sa lsym p tom s: Im p roved sc ore:19 Unc ha nged sc ore:0 W orse sc ore:3 Na sa lsigns: Im p roved sc ore:15 Unc ha nged sc ore:7 W orse sc ore:0 Eye sym p tom s: Im p roved sc ore:13 Unc ha nged sc ore:4 W orse sc ore:5 Na ya k 1/0/79 Mea n d ifferenc es in p la sm a c ortisollevels b etween Pa tientrep ort 1998 b a seline a tweek 6: 0hrs: T AA220g:-1. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year To talwithdrawals; Co untry Adverseeffects withdrawalsdueto adverse TrialName repo rted events Co mments H ill None rep orted 0;0 1978 Na ya k Perc enta ge ofp a tients rep orting a d verse 0;0 1998 events: T AA220g/d :54% T AA440g/d :42% Pla c eb o:35% NCS Page 290 of 357 Final Report Update 1 Drug Effectiveness Review Project EvidenceTable7. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Co untry Studydesign TrialName Setting Eligibilitycriteria Interventio ns Run-in/washo utperio d Neum a n Doub le-b lind , Child ren a ged 9-18yea rs, b ec lom etha sone d ip rop iona te NR/NR 1978 c rossover with p erennia la llergic rhinitis a nd 50g inha led in ea c h nostril,4 d a ilysym p tom s ofsneezing, tim es d a ily rhinorrhoea a nd na sa lob struc tion S tud yp eriod :6weeks fora tlea st5yea rs Nga m p ha ib oon Ra nd om ized d oub le- Child ren a ged 5-11yea rs with m od flutic a sone p rop iona te 100m c g NR/2week wa shoutb etween 1997 b lind ,single d ose, vs p la c eb o trea tm ents T ha ila nd p la c eb o-c ontrolled , S tud yp eriod :4weeks,with 2 p a ra llel weeks a d d itiona lfollowup m ultic enter S a rsfield Ra nd om ized , Child ren with p erennia l Na sa lflunisolid e vs p la c eb o NR/NR 1979 d oub le-b lind ,c rossover a rthritis S tud yp eriod :2m onths stud y T hen 17p a tients resp ond ing wellwith fluc isolid e c ontinued trea tm entfora d d itiona l6m onth, op en p eriod NCS Page 291 of 357 Final Report Update 1 Drug Effectiveness Review Project EvidenceTable7. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Metho do fo utco me Age Numberscreened/ Co untry Allo wedo thermedicatio ns/assessmentandtimingo fGender Otherpo pulatio n eligible/ TrialName interventio ns assessment Ethnicity characteristics enro lled Neum a n NR Da ilyd ia ryc a rd s, 13. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Number Co untry withdrawn/ Metho do fadverseeffects TrialName lo stto fu/analyzedOutco mes assessment Neum a n NR/NR/NR Mea n d a ilyna sa lsym p tom sc ores: Pa tientoutc om e,self-rep ort 1978 W eek 1:BD:1. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year To talwithdrawals; Co untry Adverseeffects withdrawalsdueto adverse TrialName repo rted events Co mments Neum a n None Rep orted NR;NR 1978 Nga m p ha ib oon None rep orted 0;0 1997 T ha ila nd S a rsfield Mostc om m on a d verse events rep orted : 1;1 1979 tra nsientna sa lstinging After6m onth op en-p eriod ,m ea surem ents of0900b lood c ortisolc onc entra tions found no effec t. NCS Page 294 of 357 Final Report Update 1 Drug Effectiveness Review Project EvidenceTable7. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Co untry Studydesign TrialName Setting Eligibilitycriteria Interventio ns Run-in/washo utperio d S hore Ra nd om ized ,d oub le- Child ren a ged 4-12yea rs, Intra na sa lb ec lom etha sone vs NR/3week wa shoutb etween 1976 b lind ,p la c eb o-c ontrolled ,with p erennia la llergic rhinitis for p la c eb o trea tm ents c ross-over over1yea r,fa ilure to resp ond to S tud yp eriod :4m onths single-c enter sod ium c rom oglyc a te insuffla tion a nd hyp osensitiza tion, p retrea tm entob serva tion a tstud y c linic fora tlea st6m onths, sym p tom a tic a tsc reening, ra d iologic a lstud ies exc lud ing a b norm a lities c a using ob struc tion,ina d eq ua te p revious resp onse to trea tm ent S torm s Ra nd om ized ,d oub le- Pa tients a ged 12-65yea rs,with tria m c inolone a c etonid e na sa l NR/NR 1991 b lind ,p la c eb o-c ontrolled ,p erennia la llergic rhinitis fora t sp ra y,110g vs 220g vs 440g p a ra llel lea st2yea rs,p oorresp onse to onc e d a ilyvs p la c eb o Multi-c enter a ntihista m ines a nd /or S tud yp eriod :12weeks d ec ongesta nts or im m unothera p y,p ostive skin p ric k testfora tlea sta llergin Exc lusion:p regna nc yorla c ta tion, use ofna sa lc rom olyn T od d Ra nd om ized , Child ren with p erennia l fluisolid e na sa lsp ra y50g three NR/NR 1983 d oub le-b lind ,c ross-over rhinitis tim es d a ily,vs p la c eb o S tud yp eriod :8weeks NCS Page 295 of 357 Final Report Update 1 Drug Effectiveness Review Project EvidenceTable7. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Metho do fo utco me Age Numberscreened/ Co untry Allo wedo thermedicatio ns/assessmentandtimingo fGender Otherpo pulatio n eligible/ TrialName interventio ns assessment Ethnicity characteristics enro lled S hore Pa tients a llowed to Da ilysym p tom d ia ry 8yea rs Allergyto gra ss extra c t:36% NR/NR/46 1976 c ontinue usua la ntihista m ine results rec ord ed a tc linic 78. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year Number Co untry withdrawn/ Metho do fadverseeffects TrialName lo stto fu/analyzedOutco mes assessment S hore 2/0/44 Results rec ord c a rd s ofb ec lom eta sone: Pa tientd a ilysym p tom d ia ry 1976 S uc c ess:38(86%) Fa ilure:6 S torm s 0/0/305 Mea n Cha nges from Ba seline in S ym p tom s S c ores: Pa tientoutc om e,self-rep ort 1991 W eek 6: Na sa lS tuffiness:110m c g:-0. T od d NR/NR/64 Cha nges in sym p tom a tolgyfrom b a seline to 8weeks- Ind irec tq uestionning a t 1983 p -va lue ofd ifferenc e b etween trea tm enta nd p la c eb o: c linic visits S neezing:p =0. Placebo -co ntro lledtrialsinchildrenwithPAR Autho r Year To talwithdrawals; Co untry Adverseeffects withdrawalsdueto adverse TrialName repo rted events Co mments S hore None rep orted 2;0 1976 S torm s Ad verse events rep orted : 0;0 1991 H ea d a c he:T 200:16% vs T 400:18% vs T 800:21% vs p la c eb o:18% Up p erresp ira toryinfec tion:T 200:4% vs T 400:5% vs T 800:7% vs p la c eb o:13% Ep ista xis:T 200:3% vs T 400:3% vs T 800: 4% vs p la c eb o:9% T hroa td isc om fort:T 200:1% T od d Na sa lirrita tion:F:12vs p la c eb o:10 NR;NR 1983 Eyes running:F:3vs p la c eb o:1 Nose b leed :F:1vs p la c eb o:1 Itc h:F:2vs p la c eb o:0 Na usea :F:1vs p la c eb o:0 H ea d a c he:F:2vs p a c eb o:2 S leep y:F:0vs p la c eb o:1 Ra sh:F:0vs p la c eb o:1 NCS Page 298 of 357 Final Report Update 1 Drug Effectiveness Review Project Ev id enc eTable8. Qualityassessm entofplac ebo-c ontrolled trials in c h ild ren with PAR InternalValidity R eporting of attrition, Auth or, Alloc ation Elig ibility Outc om e c rossov ers, Year, R and om ization c onc ealm ent Groups sim ilar c riteria assessors Careprov id er Patient ad h erenc e,and Country ad equate? Qualityassessm entofplac ebo-c ontrolled trials in c h ild ren with PAR ExternalValidity Auth or, Loss to follow- Intention-to- Post- Num bersc reened / Year, up: treat(ITT) rand om ization Quality elig ible/ Country d ifferential/h ig h analysis exc lusions rating enrolled Exc lusion c riteria R un-in/wash out Day No Ye s No Fair NR/NR/107adults Pre gnancy,tube rculosis,re spiratory 2-w e e k base line pe riod 1990 andchildre n infe ction,additional nasal dise ase or w he re patie nts asthm are quiringtre atm e ntw ith re corde dsym ptom s corticoste roids andre ce ive donly te rfe nadine (60m gup to tw o table ts pe rday Fok k ens No Ye s No Fair NR/NR/202 Pollle n alle rgyin se ason,uppe r 1-w e e k base line pe riod 2002 re spiratoryinfe ction w ithin 2w k s in w hiche fficacy be fore scre e ning,rhinitis variable s w e re m e dicam e ntosaorstructural m e asure dtw ice daily abnorm alitie s sym ptom atice e nough to cause significantnasal obstruction, unstable asthm a,im m unothe rapynot on constantm ainte nance dose ,any othe rsignificantdise ase s,syste m ic corticoste roidthe rapyw ithin 2 m onths,e x te nsive application of topical cutane ous ste roids,topical nasal ste roids w ithin one m onth be fore scre e ning,othe rm e dication possiblyinte rfe ring:antihistam ine s w ithin 3days,crom oglycate w ithin 2 w k s,aste m izole w ithin 1m onth be fore scre e ning Hill No Ye s No Fair NR/NR/22 None re porte d No 1978 NCS Page 300 of 357 Final Report Update 1 Drug Effectiveness Review Project Ev id enc eTable8. Qualityassessm entofplac ebo-c ontrolled trials in c h ild ren with PAR Class Control Auth or, naïv e g roup Year, patients stand ard of Country only c are Fund ing R elev anc e Day No N/A One authoris from Ye s 1990 ABDraco,Lund, Sw e de n Fok k ens No N/A Financial support Ye s 2002 from AstraZe ne ca R&D,LundSw e de n Hill No N/A NR Ye s 1978 NCS Page 301 of 357 Final Report Update 1 Drug Effectiveness Review Project Ev id enc eTable8. Qualityassessm entofplac ebo-c ontrolled trials in c h ild ren with PAR InternalValidity R eporting of attrition, Auth or, Alloc ation Elig ibility Outc om e c rossov ers, Year, R and om ization c onc ealm ent Groups sim ilar c riteria assessors Careprov id er Patient ad h erenc e,and Country ad equate? Qualityassessm entofplac ebo-c ontrolled trials in c h ild ren with PAR ExternalValidity Auth or, Loss to follow- Intention-to- Post- Num bersc reened / Year, up: treat(ITT) rand om ization Quality elig ible/ Country d ifferential/h ig h analysis exc lusions rating enrolled Exc lusion c riteria R un-in/wash out Nayak no ye s no fair NR/NR/80 Anyclinicallyre le vantde viation from no 1998 norm al m e dical orlaboratory USA param e te rs,an intole rance to corticoste roidthe rapy,anym e dical condition capable ofalthe ringthe pharm acok intics ofthe drup,acute infe tiors sinusitis,unde rlyingnasal pathologyre sultingin occlusion ofa nostril,visible e vide nce offungal infe ctionn ofthe nose ,throat,or m outh,oran initial m orningplasm a cortisol le ve l outside the range of5to 20m cg/dl. Also patie nts tre ate dw ithsyste m ic corticoste roids w ithin 90d,oral corticoste roids form ore than 10d w ithin the pastye ar,orifthe y participate din anyinve stigational drugstudyw ithin 60doranypre vious studyw ithtriam cinolone aque sous nasal spray. Neum an no notcle ar no poor NR/NR/30 NR no 1978 Israel NCS Page 303 of 357 Final Report Update 1 Drug Effectiveness Review Project Ev id enc eTable8. Qualityassessm entofplac ebo-c ontrolled trials in c h ild ren with PAR Class Control Auth or, naïv e g roup Year, patients stand ard of Country only c are Fund ing R elev anc e Nayak no ye s Supporte din partby ye s 1998 Rhone -Poule ncrore USA Pharace uticals,Inc. Neum an no ye s NR ye s 1978 Israel NCS Page 304 of 357 Final Report Update 1 Drug Effectiveness Review Project Ev id enc eTable8. Qualityassessm entofplac ebo-c ontrolled trials in c h ild ren with PAR InternalValidity R eporting of attrition, Auth or, Alloc ation Elig ibility Outc om e c rossov ers, Year, R and om ization c onc ealm ent Groups sim ilar c riteria assessors Careprov id er Patient ad h erenc e,and Country ad equate? Qualityassessm entofplac ebo-c ontrolled trials in c h ild ren with PAR ExternalValidity Auth or, Loss to follow- Intention-to- Post- Num bersc reened / Year, up: treat(ITT) rand om ization Quality elig ible/ Country d ifferential/h ig h analysis exc lusions rating enrolled Exc lusion c riteria R un-in/wash out Ng am ph aiboon No Ye s No Fair NR/NR/106 Physical obstruction in the nose , No 1997 concurre ntdise ase s thatw ouldaffe ct the irabilityto participate safe lyand fullyin the study,hype rse nsitivityto anycorticoste roid,use ofanyste roid, sodium crom oglycate orne docrom il sodium 2w e e k s be fore e nrollm e nt, oral aste m izole 6w e e k s be fore the study,hypose nsitization tre atm e nt duringthe pre vious 12m onths,or concurre ntinfe ction ofparanasal sinuse s oruppe rorlow e rre spiratory tract. Sarsfield no ye s no fairto poor NR/NR/27 NR Notre porte d 1979 UK Sh ore No Ye s No Fair NR/NR/46 None re porte d 1-w e e k w ashout 1977 be tw e e n cross-ove r NCS Page 306 of 357 Final Report Update 1 Drug Effectiveness Review Project Ev id enc eTable8. Qualityassessm entofplac ebo-c ontrolled trials in c h ild ren with PAR Class Control Auth or, naïv e g roup Year, patients stand ard of Country only c are Fund ing R elev anc e Ng am ph aiboon No N/A Financial support Ye s 1997 from Glax o T hailand Sarsfield no ye s NR ye s 1979 UK Sh ore No N/A NR Ye s 1977 NCS Page 307 of 357 Final Report Update 1 Drug Effectiveness Review Project Ev id enc eTable8. Qualityassessm entofplac ebo-c ontrolled trials in c h ild ren with PAR InternalValidity R eporting of attrition, Auth or, Alloc ation Elig ibility Outc om e c rossov ers, Year, R and om ization c onc ealm ent Groups sim ilar c riteria assessors Careprov id er Patient ad h erenc e,and Country ad equate? Qualityassessm entofplac ebo-c ontrolled trials in c h ild ren with PAR ExternalValidity Auth or, Loss to follow- Intention-to- Post- Num bersc reened / Year, up: treat(ITT) rand om ization Quality elig ible/ Country d ifferential/h ig h analysis exc lusions rating enrolled Exc lusion c riteria R un-in/wash out Storm s no ye s no fair NR/NR/137 Anyclinical de viation from norm al no 1996 m e dical orlabparam e te rs,nasal candiasis,acute sinusitis,orahistory ofhype rse nsitivityto corticoste roids Anyofthe follow ingconditions: tre atm e ntw ithnasal,inhale dor syste m iccorticoste roids w ithin 42 days priorto the study,nasal crom olyn sodium w ithin 14d, m e dication thatm ightproduce or re lie ve sym ptom s ofalle rgicrhinitis, oran inve stigational drugw ithin 90d, initiation ofim m unothe rapyw ithin 30d orparticipation in anypre vious T riam cinolone trials. Tod d no no No fair NR/NR/64 None re porte d No 1983 NCS Page 309 of 357 Final Report Update 1 Drug Effectiveness Review Project Ev id enc eTable8. Qualityassessm entofplac ebo-c ontrolled trials in c h ild ren with PAR Class Control Auth or, naïv e g roup Year, patients stand ard of Country only c are Fund ing R elev anc e Storm s no N/A funde dbyRhone - ye s 1996 Poule ncRore r Pharm ace uticals Tod d No N/A Mate rials supplie d ye s 1983 bySynte x Pharm ace uticals Ltd. NCS Page 310 of 357 Final Report Update 1 Drug Effectiveness Review Project Ev id enc eTable8. Qualityassessm entofplac ebo-c ontrolled trials in c h ild ren with PAR InternalValidity R eporting of attrition, Auth or, Alloc ation Elig ibility Outc om e c rossov ers, Year, R and om ization c onc ealm ent Groups sim ilar c riteria assessors Careprov id er Patient ad h erenc e,and Country ad equate? Qualityassessm entofplac ebo-c ontrolled trials in c h ild ren with PAR ExternalValidity Auth or, Loss to follow- Intention-to- Post- Num bersc reened / Year, up: treat(ITT) rand om ization Quality elig ible/ Country d ifferential/h ig h analysis exc lusions rating enrolled Exc lusion c riteria R un-in/wash out Welc h no no NR fair NR/NR/210 Use oforal orpare nte ral Base line pe riodof6- 1991 corticoste roids w ithin 60dpriorto 10d,no rhinitis study,orlong-actingde potste roids m e dication w as w ithin 6m onths,use ofnasal allow e dduringthe last corticoste roids ornasal crom olyn 5d w ithin 30dofthe study,anye vide nce ofinfe ction,sinusitis,otitis m e dia, nasal polyps oranyfix e danatom ical abnorm alityandlack ofstabilization w ithim m unothe rapy NCS Page 312 of 357 Final Report Update 1 Drug Effectiveness Review Project Ev id enc eTable8. Qualityassessm entofplac ebo-c ontrolled trials in c h ild ren with PAR Class Control Auth or, naïv e g roup Year, patients stand ard of Country only c are Fund ing R elev anc e Welc h no N/A Supporte dbyagrantye s 1991 from Rhone -Poule nc Rore r Pharm ace uticals NCS Page 313 of 357 Final Report Update 1 Drug Effectiveness Review Project EvidenceTable9. Trialsinpatientswithnon-allergicrhinitis Allowedother Author Studydesign Run-in/washout medications/ Year Setting Eligibilitycriteria Interventions period interventions Lundb lad Random ized,doub le- Patients ag ed18-82years w ith m om etasonefuroate N R/N R Proh ib ited:topic alnasal, 2001 b lind,plac eb o-c ontrolledperennialnon-allerg ic rh initis, nasalspray,200m c g oc ularororal Multi-c enter unspec ific rh initis sym ptom s onc edailyv s plac eb o dec ong estants,nasal Exc lusion:Positiv eskin pric k tests, Studyduration:11 saline,sh ortandlong - intoleranc eto aspirin ornon- w eeks ac ting anti-h istam ines, steroidalanti-inflam m atorydrug s, nasalatropineor struc turalab norm alilties,nasal ipratropium b rom ide, polyps ketotifen,azelastineand intransaloroc ular c ortic osteroids for1-2 w eeks,inv estig ational drug s Web b 3random ized,plac eb o-Patients ag ed>11years,w ith intranasalflutic asone N R/N R N R 2002 c ontrolled,doub le-b lind,perennialrh initis w ith orw ith out propionate,200g paralleltrials eosinoph ilia,neg ativ eskin tests to dailyv s 400g dailyv s Multi-c enter allallerg ins relev antto g eog raph ic plac eb o reg ion Studyperiod:4 w eeks NCS Page 314 of 357 Final Report Update 1 Drug Effectiveness Review Project EvidenceTable9. Trialsinpatientswithnon-allergicrhinitis Number Methodofoutcome Age screened/ Author assessmentandtimingofGender Other population eligible/ Number withdrawn/ Year assessment Ethnicity characteristics enrolled losttofu/analyzed Outcomes Lundb lad Patientdailydiaryof N R N R N R/N R/329 N R/N R/N R Im prov em entrates:Patient 2001 sym ptom s report PP:MFN S:69/119(58%)v s plac eb o:62/132(47%) ITTg roup:MFN S:93/167 (56%)v s plac eb o:80/162 (49%) Im prov em entrates: Inv estig atorreport PP:MFN S:74/119(62%)v s plac eb o:61/132(46%) ITTg roup:100/167(60%)v Web b N asalc osinoph ildev aluated42years Duration of rh initis: N R/N R/983 <2%/N R/95% Im prov em entin TN SSb oth 2002 w ith 5-pointsc ale,total 37% Male plac eb o v s F200v s F200g and400g ,eac h w eek nasalsym ptom sc ore 94% F400: v s plac eb o:p<0. Trialsinpatientswithnon-allergicrhinitis Methodof Totalwithdrawals; Author adverseeffects withdrawalsdueto Year assessment Adverseeffectsreported adverseevents Lundb lad Patientself-report Adv erseev ents reported: N R;N R 2001 Upperrespiratoryinfec tion: MFN S:27. Qu alityas s es s ment o f trials inp atients w ithno n-allergicrhinitis Internal Validity Rep o rtingo f attritio n, Lo s s to Intentio n- Au tho r, Allo catio n Gro u p s Eligibility Ou tco me Care cro s s o v ers , fo llo w -u p : to -treat Po s t- Year Rando mizatio n co ncealment s imilarat criteria as s es s o rs p ro v ider Patient adherence,and differential/ (ITT) rando mizatio n Co u ntry adequ ate? Qu alityas s es s ment o f trials inp atients w ithno n-allergicrhinitis External Validity Nu mber Clas s Co ntro l Au tho r, s creened/elig naïv e gro u p Year Qu ality ible/ Ru n-in/ p atients s tandard Co u ntry rating enro lled Exclu s io ncriteriaWas ho u t o nly o f care Fu nding Relev ance Lu ndblad Fair NR/NR/329 Aspirin 2-w eek No Yes NR Yes 2001 intolerance screening Sw eden, ornon- period Norw ay, steroidalanti- Finland, inflammatory Denmark dru gs. Significant septal dev iationsor otherstru ctu ral deformitiesor nasalpolyps. Webb Fair NR/NR/983 Useof other 7-day No Yes Su pportedin Yes 2002 rhinitis screening part by USA medication period SmithKline Beecham Corporation doing bu sinessas GlaxoSmith Kline NCS Page 318 of 357 Final Report Update 1 Drug Effectiveness Review Project EvidenceTab le11. Ob s ervatio nal s tudies Pro s p ective Autho r,year Retro s p ective Exp o s ure Co untry Datas o urce Unclear p erio d Meanduratio no ffo llo w-up Derby ,2000 U K-based General Retrospective 1991-1996 Estim ated from graph,person y earsof U K P ractice Research follow up Database by age and treatm entcohort Intranasal: <20y :21,000 20-39y :31,500 40-59y :27,000 60+y :10,500 U nexposed: <20y :25,000 20-39y :34,000 40-59y :30,000 60+y :11,500 Koepk e,1997 O pen-labelcontinuation P rospective 12m onths,specific 94. Ob s ervatio nal s tudies Age Exp o s ed Autho r,year Interventio ns Gender Eligib le Co untry Meando s e Po p ulatio n Ethnicity Selected Derby ,2000 Exposure tointranasal Lessthan 70y earsold in 1993 Intranas al co rtico s tero idus ers : N R,N R,n=286,078 U K corticosteroidsonly withouta history ofasthm a or m ean age N R,25% aged 50orolder (beclom ethasone,fluticasone, chronic obstructive pulm onary 56% fem ale budesonide)ororalcorticosteroids disease (exceptfororalsteroids ethnicity N R only ornotexposed toany cohort) unexp o s edco ho rt: corticosteroids to tal s tudy p o p ulatio n:286,078 m ean age N R,25% aged 50orolder intranas al co rtico s tero idus ers : 51% fem ale 88,301,about70% used ethnicity N R beclom ethasone only o ral co rtico s tero idus ers : o ral co rtico s tero idus ers :98,901,m ean age N R,50% aged 50orolder 41% had nopreviousevidence of 56% fem ale eitherasthm a orCO P D ethnicity N R unexp o s edco ho rt:98,876 Koepk e,1997 220m cg triam cinolone aqueous/day Adolescentand adultpatientswith M ean age:31y ears(range,11-59y ears)N R,178,n=172 U SA with an option toreduce to110m cg atleast2y earhistory ofperennial 37% fem ale and 64% m ale triam cinolone/day ifsy m ptom s allergic rhinitis 98% white were controlled NCS Page 320 of 357 Final Report Update 1 Drug Effectiveness Review Project EvidenceTab le11. Ob s ervatio nal s tudies Withdrawn Autho r,year Lo s tto fu Co untry Analyzed Effectivenes s o utco mes Derby ,2000 N /A N /A U K Koepk e,1997 34/5/172 M ean changesin visualanalog scale scoresfrom the startofdouble-blind treatm ent U SA M ean Im provem entin sy m ptom scom pared tothe double-blind baseline m ean (estim ated from figure),all p<0. Ob s ervatio nal s tudies Autho r,year Co untry Safety o utco mes Co mments Derby ,2000 Numb er o fcas es o fcataract F unded by U K Intranasalcorticosteroid users:217in 208,753person-y ears GlaxoW ellcom e Inc. Beclom ethasone only :140in 140,831person-y ears U nexposed cohort:213in 206,560person-y ears O ralcorticosteroid users:629in 289,371person-y ears Subjectswithoutasthm a:274in 91,064person-y ears Incidencerate/1000p ers o n-years (95% CI) Intranasalcorticosteroid users:1. Ob s ervatio nal s tudies Pro s p ective Autho r,year Retro s p ective Exp o s ure Co untry Datas o urce Unclear p erio d Meanduratio no ffo llo w-up M ansfield,2002 P ediatric clinicalrecords Retrospective 12m onthsto91 36m onths U SA m onths,specific dates notreported M oller,2003 SixSwedish pediatric P rospective,24-m onth N R 73children com pleted 1y earand 33- Sweden clinics,open,non- observation 37children com pleted 24m onths controlled trial Lange,2005 study prospective 2003grasspollen m ean N R Germ any season 4-week study NCS Page 323 of 357 Final Report Update 1 Drug Effectiveness Review Project EvidenceTab le11. Ob s ervatio nal s tudies Age Exp o s ed Autho r,year Interventio ns Gender Eligib le Co untry Meando s e Po p ulatio n Ethnicity Selected M ansfield,2002 beclom ethasone aqueous168m cg Children with perennialallergic M ean age:70m onths(range,24- N R,N R,n=60 U SA twice daily with occasionaldosing rhinitiswith seasonal 117m onths) of168m cg once daily exacerbations 20girls(33. In the steroidsin previous3m onthswere 22girls(28%) second y earreductionsto200m cg excluded Seco ndyear were allowed. Ob s ervatio nal s tudies Withdrawn Autho r,year Lo s tto fu Co untry Analyzed Effectivenes s o utco mes M ansfield,2002 N /A N R U SA M oller,2003 9subjectswithdrawn Severity and duration ofalldaily nasalsy m ptom s(4-pointscale):reduced com pared topre-treatm ent, Sweden (5in y ear1and 4in p<0. Ob s ervatio nal s tudies Autho r,year Co untry Safety o utco mes Co mments M ansfield,2002 Growth m easured by stadiom etry F unding sourcesN R U SA M easured m ean heightatentry :149. Disodium Crom ogly cate Germ any P atientswith lessthan one AE18vs. Ob s ervatio nal s tudies Pro s p ective Autho r,year Retro s p ective Exp o s ure Co untry Datas o urce Unclear p erio d Meanduratio no ffo llo w-up P itsios,2006 study prospective Spring 2002 m ean N R Greece treatm entstarting 2-4week sbefore pollen season and continuing forupto 4m onths NCS Page 327 of 357 Final Report Update 1 Drug Effectiveness Review Project EvidenceTab le11. Ob s ervatio nal s tudies Age Exp o s ed Autho r,year Interventio ns Gender Eligib le Co untry Meando s e Po p ulatio n Ethnicity Selected P itsios,2006 400m cg M om etasone furorate once seasonalallergic rhinitishistory of m ean age:28. Ob s ervatio nal s tudies Withdrawn Autho r,year Lo s tto fu Co untry Analyzed Effectivenes s o utco mes P itsios,2006 none M om etasone vs. N edocrom ilsodium Greece none % ofday swith m inim alsy m ptom sasm easured using totalnasalsy m ptom scores,86% vs.

However buy glucotrol xl 10mg low cost diabetes mellitus education, up to 24% of men with SCD may develop delayed puberty in males contributes to sperm abnormalities in hypogonadism discount 10mg glucotrol xl fast delivery diabetes mellitus canine, a clinical syndrome associated with poor testos- those 25 years of age order glucotrol xl 10 mg mastercard diabetes prevention control, these abnormalities improve in older men terone production order glucotrol xl 10 mg visa blood sugar 25, infertility, ED, and poor libido. Clinical laboratory findings are low testos- ties are reported even when testosterone, FSH, and LH are normal. It is reprinted with permission from Blood 2014, Volume 124. These high rates may be due to many factors, needed to determine the clinical importance of abnormal sperm including barriers to contraception access, failure of contraception analysis and its impact on male fertility in SCD. Barriers to access may be at the physician level because physicians may be underprescribing hor- ED monal contraceptives. Studies reporting physicians’ prescribing ED occurs frequently in men with SCD, with prevalence rates as patterns for contraception and patient preferences for contraception high as 21%–35% reported. Management of ED due to priapism depends on the extent of penile tissue fibrosis. Contraception choices for women with SCD Penile implants have been used successfully, but multiple complica- 21,22 Combined hormonal contraceptive agents. A general clinical philosophy is that prevention monal contraceptive use in patients with SCD has been fraught with is better than treatment because of the relatively poor outcomes of concerns regarding thrombotic complications and increased pain. Therapeutic Theoretical concerns are related to the underlying pathophysiology strategies to limit the duration of priapism events and to prevent of SCD and its “prothrombotic” state. Abnormal RBC rheology, priapism recurrences should be used aggressively. These factors may lead to increased venous stasis, studies have addressed this topic prospectively using standard clotting, and pain in women with SCD receiving estrogen. Although the studies are small, 150 individual patients may reproductive years as a surrogate for fertility. Thrombotic rates of patients with SCD and healthy controls have been com- events have been reported to occur in a small number of pa- pared, the lower number of pregnancies in women with SCD has tients. Presently, we understand that many factors other than infertility may have influenced the number of pregnancies per patient. Progestin-only con- supported by studies finding similar conception rates in women with traceptives should be a good choice in women with SCD due to a SCD and healthy controls. One of the biggest menstrual bleeding in women with SCD is its association with an barriers to progesterone-only medication is its side effect profile, increased SCD-related pain rate. These progesterone- women, increased SCD-related pain occurs at different stages of the only compounds have changed over the years to narrow the side menstrual cycle and this pattern may be related to fluctuations in the effects, and this limits the ability to compare data between levels of estrogen and progesterone. Progesterone used as daily oral or As mentioned in earlier sections, progesterone was reported to depot preparations decreases SCD-related painful events in a subset decrease the frequency of acute pain in women with SCD as early of women. After preliminary studies of progesterone and testoster- one demonstrated decreased sickling, investigators performed a Sexuality and reproductive choices in women with SCD crossover study in 28 women treated with progesterone and 16 Information on sexuality in women with SCD is limited. Although results were prelimi- the well-described data on delayed puberty and adverse outcomes nary, they reported an 80% reduction in pain in the treated group. However, attitudes regarding contraception and unplanned placebo either before or after depot medroxyprogesterone acetate pregnancy suggest that women with SCD are interested in avoiding (DMPA). In addition, hemoglobin, fetal hemoglobin, and general population. This led to the Unplanned pregnancy and SCD conclusion that improved RBC survival may be due to the Unplanned pregnancy remains high globally and contraceptive use increased survival of RBCs containing higher concentrations of varies widely by country, age, and race/ethnicity. Finally, de Abood et al reported 43 women SCD, unplanned pregnancy rates have been high historically and with SCD who had pain in the last year and were nonrandomly remain high. Hematology 2014 419 Use of implantable progesterone-only containing compounds has although 2 women had successful pregnancies, 1 after preimplanta- been reported in small prospective studies in women with SCD. In 2004, the World unpredictable risk of infertility, patients may opt for procedures to Health Organization released recommendations on the use of preserve fertility before HSCT regardless of conditioning regimens. Although experience is limited, patients with IUDs outweighed the risks associated with the increased morbidity SCD have success with procedures and therapies that preserve and mortality associated with pregnancy. Cryopreservation options have expanded and depend Eligibility Criteria for Contraceptive Use 2010 continues to support 49 on stage of pubertal development. Combined hormonal contraceptives are pubertal males is standard and improvement of sperm banking classified as level 2, meaning that “the advantages of using the techniques and increased use of intracytoplasmic sperm injection method generally outweigh the theoretical or proven risks. Cryopreservation of testicular terone-only containing pills are classified as level 1, meaning that tissue, considered experimental, is an option in prepubertal boys, these agents can be used without restrictions. However, it is but is waiting for the development of technology and procedures for concerning that these recommendations are based primarily on the 63 restoring human fertility. It should be noted, however, that reduced SCD-related morbidity. However, as utilization of these women with SCD are at risk for thromboses67 and increased acute therapies increases, more attention is drawn to their associated pain while being exposed to increased estrogen levels during adverse effects and toxicities. Issues have been raised regarding HU ovarian stimulation. Successful oocyte preservation after controlled use, abnormal sperm production, and teratogenic effects. In addi- ovarian stimulation in a 19-year-old woman with SCD has been tion, fertility preservation after HSCT and the endocrine abnormali- described using a protocol to avoid hyperstimulation and incorporat- ties associated with transfusional iron overload remain concerns. In addition, successful pregnan- contraception counseling is paramount to decreasing unplanned cies in women with SCD after ovarian tissue preservation have been pregnancies. Hormonal contraceptive use is controversial in SCD 61,62 reported. For girls who are 18 years of age, particularly those primarily due to the theoretical increased risk for venous thrombo- 12 years, ovarian tissue preservation is an option, although embolism and risk for acute pain events. When counseling pediatric 68 outcomes in SCD are not clear. Transfusional iron overload and infertility Patterns of transfusional iron overload in patients with SCD seem to HSCT and fertility preservation be different from those in patients with thalassemia. HSCT remains the sole cure for SCD, with event- free survival rates averaging 85%–90% for allogeneic transplanta- Transfusional iron overload, if untreated, may lead to infertility tions. Gonadal failure in patients with SCD on outcomes such as endocrine dysfunction and impaired fertility are chelation therapy occurs at similar rates in those with SCD without iron overload. If the toxicity of conditioning regimens could be decreased while maintaining low rates of graft rejection, delayed in patients with SCD receiving chronic transfusion therapy HSCT may be considered more often in patients with SCD before compared with patients with thalassemia major. Generally, focus is severe acute complications and major end-organ damage occur. In women with Myeloablative conditioning regimens before HSCT for SCD cause thalassemia major, biomarkers have been used to assess reproduc- infertility, particularly in females. Young children who receive SCD receiving HU is impressive. Its impact on reducing acute HU appear to have normal growth,75 but information on pubertal complications and improving survival suggests that HU may development is less clear. However, 2 reproductive issues loom have a positive effect at limiting SCD-related organ dysfunction with the use of HU in both the pediatric and adult populations: long term. Furthermore, some clinicians suggest that HU’s abnormal spermatogenesis and teratogenic effects. Published litera- positive impact on vasoocclusive events may limit testicular ture on these topics is limited. Much information is in case reports infarction and improve spermatogenesis. This makes evidence-based counseling on the risk of developing Nevertheless, more information is needed on the impact of HU on sperm abnormalities or infertility on HU challenging. Counseling patients before HU initiation is challenging given this lack of information.

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